DOI:http://dx.doi.org/10.7314/APJCP.2013.14.8.4495 Health Claims Made for Noni and Current Scientific Knowledge

MINI-REVIEW

Do the Health Claims Made for (Noni) Harmonize with Current Scientific Knowledge and Evaluation of its Biological Effects Rakesh Kumar Gupta1*, Amit Kumar Patel2

Abstract

Morinda citrifolia, also known as Great Morinda, Indian Mulberry, or Noni, is a plant belonging to the family Rubiaceae. A number of major chemical compounds have been identified in the leaves, roots, and fruits of the Noni plant. The fruit is in high demand in for different kinds for illnesses such as arthritis, diabetes, high blood pressure, muscle ached and pains, menstrual difficulties, headache, heart diseases, AIDS, gastric ulcer, sprains, mental depression, senility, poor digestion, arteriosclerosis, blood vessel problems, and drug addiction. Several studies have also demonstrated anti-inflammatory, antioxidant and apoptosis-inducing effects of Noni in various . Based on a toxicological assessment, Noni juice was considered as safe. Though a large number of in vitro, and, to a certain extent, in vivo studies demonstrated a range of potentially beneficial effects, clinical data are essentially lacking. To what extent the findings from experimental pharmacological studies are of potential clinical relevance is not clear at present and this question needs to be explored in detail before an recommendations can be made.

Keywords: Morinda citrifolia (Noni) inflammation - antioxidant - - DNA repair

Asian Pac J Cancer Prev, 14 (8), 4495-4499 Introduction and roots of Noni plant are scopoletin, octoanoic acid, potassium, Vitamin C, terpenoids, alkaloids, Among the medicinal plants discovered by the anthraquinones (such as nordamnacanthal, morindone, ancestors of Polynesians, Morinda citrifolia (Noni) is rubiadin, and rubiadin-1-methyl ether, anthraquinone one of the important traditional folk medicinal plants that glycoside), linoleic acid, alizarin, amino acids, acubin, have been used for over 2000 years in Polynesia (Morton, L-asperuloside, caproic acid, Caprylic acid, ursolic acid, 1992; Serafini et al., 2011). Noni is commonly referred rutin, carotene, Vitamin A, flavones, glycosides, iridoid to the species M. citrifolia. It is also known by various glycosides, and a putative prexeronine (Pawlus et al., local names such as Nona, Nono, Nuna, Pain Bush, Pain 2005; Akihisa et al., 2007; Alitheen et al., 2010; Gupta et Killer Tree, Cheese Fruit, Forbidden Fruit, Headache al., 2013). Predominantly, fruit contains fatty acids; while Tree, Nino, Pinuela, Hog Apple, Mona, Mora de la India, the roots and bark contain anthraquinones (Alitheen et al., and Wild Pine in various parts of the world. Noni is an 2010). evergreen tree found growing in open coastal regions at sea level and in forest areas up to about 1300 feet above Noni-Based Nutritional Supplementation for sea level. It is often found growing along lava flows. Noni Weight Gain is identifiable by its straight truck, large, bright green and elliptical leaves, white tubular flowers, and its distinctive, Noni-based nutritional supplementation and exercise ovoid, “grenade-like” yellow fruit. The fruit can grow interventions positively affect body composition in size up to 12 cm or more, and has a lumpy surface without side effects and are recommended to be used in covered by polygonal-shaped sections. The seeds, which combination for combating weight gain (Palu et al., 2011). are triangular shaped and reddish brown, have an air sac attached at one end, which makes the seeds buoyant. The Probiotic Potential of Noni Juice mature Noni fruit has a foul taste and odor (Morton, 1992). One study assessed the feasibility of Noni as a raw Morinda citrifolia and its Chemical substrate for the production of probiotic Noni juice by Composition lactic acid bacteria (Lactobacillus casei and Lactobacillus plantarum) and bifidobacteria (Bifidobacterium longum). Various compounds identified in the leaves, fruits, Changes in pH, acidity, sugar content, cell survival 1Department of Biochemistry, National Medical College, Birgunj, Nepal, 2Blood Bank, Apollo Hospital, Indraprastha, Delhi, India *For correspondence: [email protected] Asian Pacific Journal of Cancer Prevention, Vol 14, 2013 4495 Rakesh Kumar Gupta and Amit Kumar Patel and antioxidant properties during fermentation were Epidemiological studies have demonstrated that monitored. All tested strains grew well on Noni juice. consumption of fruits and vegetables may reduce free- L. casei produced less lactic acid than B. longum and radical-induced oxidative damage and lipid peroxidation L. plantarum. Moreover, Noni juice fermented with B. in cigarette smokers (Wang et al., 2009; Bullo’ M et al., longum had a high antioxidant capacity that did not differ 2011). significantly (p<0.05) from that of lactic acid bacteria. Mature Noni fruit had been shown to have antioxidant Finally, they suggested that B. longum and L. plantarum capacity similar to that of navel oranges and tangerines; are optimal probiotics for fermentation with Noni juice Noni leaves similar to that of green tea. Maturation (Wang et al., 2009). increased antioxidant capacity, total phenols, and ascorbic acid content of Noni fruits, and ripening beyond maturity Medicinal use of M. citrifolia decreased all three, suggesting that mature Noni fruits are good sources of dietary antioxidants and thus supports the The Polynesians utilized the whole Noni plant for practices by Pacific traditional healers of using fruits as herbal remedies. The fruit juice of Noni has been in great internal remedies and of Noni manufacturers of processing use in alternative medicine for various illnesses such as Noni products as dietary supplements (Jian et al., 2011). arthritis, diabetes, high blood pressure, muscle ached and In one study, the leaves of the Thai Noni/Yor, (Morinda pains, menstrual difficulties, headache, heart diseases, citrifolia Linn showed antioxidant properties, giving IC50 AIDS, gastric ulcer, sprains, mental depression, senility, values of 0.20-0.35 mg/ml, thus concluding the leaves of poor digestion, arteriosclerosis, blood vessel problems, M. citrifolia may have benefit as a food supplement for drug addiction, and various cancers. Scientific evidence antioxidative activities in epidermoid and cervical cancers of the benefits of the Noni fruit juice is limited but there is as compared to Damnacanthal, rutin, and scopoletin some anecdotal evidence for successful treatment of colds (Thani et al., 2010). and influenza (Basar et al., 2010; Gilani et al., 2010). Several polyphenols belonging to the coumarin, flavonoid, and phenolic acid groups, and two iridoids in Anti-inflammatory Activity of Noni Noni juice have demonstrated a mean range free radical scavenging capacity, thus showing antioxidant properties Several polyphenols belonging to the coumarin, (Dussossoy et al., 2011). Flavonoids and phenolics acid groups, and two iridoid As noted earlier, molecular epidemiologic studies have present in Noni juice have demonstrated reduced demonstrated that SAR and LOOH levels in smokers carrageenan-induced paw edema, directly inhibited are significantly higher than in nonsmokers (van et al., cyclooxygenase COX-1 and COX-2 activities and 2004). The results of one trial substantiate the antioxidant inhibited the production of nitric oxide (NO) and properties of Noni juice observed in vitro and in vivo, as prostaglandins E(2) (PGE(2)) in activated J774 cells, well as demonstrate an effect under conditions of oxidative in a dose dependent manner. This study showed that stress produced by heavy smoking (Wang et al., 2009). Noni’s biological effects include anti-inflammatory action It is highly possible that several compounds of different through NO and PGE (2) pathways that might also be polarity may contribute to the antioxidant activity of M. strengthened by anti-oxidant effects (Dussossoy et al., citrifolia fruit juice (Noni). Part of the antioxidant activity 2011). Together, the results suggested that properties may be due to lipid soluble polyphenols, anthraquinones, of M. citrifolia extract should be explored further in α-tocopherol, and β-carotene present in Noni as many order to achieve newer tools for managing painful and natural phytochemicals have been demonstrated to inflammation conditions, including those related to promote antioxidant in cancer cells, including phenolics, oxidant states. Several compounds of Noni juice have also alkaloids, damnacanthal, and flavonoids (Alshawti et been found to exhibit potent anti-inflammatory activity al., 2011; Serafini et al., 2011). It has also been reported against 12-O-tetradecanoylphorbol-13-acetate (TPA)- that most natural antioxidant compounds often work induced inflammation (1 microg/ear) in mice (Akihisa et synergistically with each other to produce a broad al., 2007). spectrum of effects against free radical attack.

Noni and Stress-induced Impairment of Noni and Ischemic stress Cognitive Function Fruit juice of Morinda citrifolia (Noni juice) is a Another finding suggested that the administration well-known health drink and has various pharmacological of Noni fruit juice protects brains from stress-induced properties including antioxidant and anti-inflammatory impairment of cognitive function and that this protective effects. One study showed that ingestion of 10% Oral effect may be related to improvement in stress-induced Noni juice (ONJ) by Male ddY mice followed by 2 h of decreases in blood vessel density in the hippocampal middle cerebral artery occlusion (MCAO) suppressed the dentate gyrus (Muto et al., 2010). development of neuronal damage; glucose intolerance observed on the 1st day after MCAO completely Antioxidant Properties of Morinda citrifolia disappeared after 10% ONJ administration; and ONJ treatment significantly increased serum insulin levels Previous research has established that fruits and much further than the control group on the 1st day, while vegetables are major sources of dietary antioxidants. serum adiponectin levels were not affected at all. These 4496 Asian Pacific Journal of Cancer Prevention, Vol 14, 2013 DOI:http://dx.doi.org/10.7314/APJCP.2013.14.8.4495 Health Claims Made for Noni and Current Scientific Knowledge results suggested that ONJ could facilitate insulin secretion mitomycin-C, bleomycin, etoposide, 5- fl uorouracil, after ischemic stress and may attenuate the development vincristine or camptothecin. It was not beneficial of glucose intolerance, suggesting that these mechanisms when combined with paclitaxel, cytosine arabinoside, may contribute to the neuronal protective effect of ONJ or immunosuppressive anticancer drugs such as against ischemic stress (Harada et al., 2010). cyclophosphamide, methotrexate or 6-thioguanine. Noni- ppt also demonstrated beneficial effects when combined Noni and Xanthine Oxidase (XO) Enzyme with the Th1 cytokine, interferon gamma, but its activity was abolished when combined with Th2 cytokines, It was elucidated that inhibitory effect of XO enzymes interleukin-4 or interleukin-10, thereby suggesting that by Noni is the mechanism by which Noni ameliorates gout Noni-ppt induces a Th1 dominant immune status in vivo. and gout-like diseases. Further, the results also support the The combination of Noni-ppt with imexon, a synthetic traditional usage of Noni in the treatment of gout (Palu et immunomodulator, also demonstrated beneficial effects al., 2009). (Furusawa et al., 2003). Several studies reported that Noni has multiple cancer Noni Rejects Tumor Cells protective properties. Oncostatic activities related to cancer prevention include reductions in TPA- or EGF- The mechanism of tumor rejection by Morinda induced cell transformation , reduction in DMBA-induced citrifolia remains unknown though the anti-tumor activity DNA damage and lesion formation (Wang and Su, 2001; of Morinda citrifolia fruit juice (Noni) has been previously Wang et al., 2002), and concentration-dependent free- reported. In another study, they demonstrated that radical scavenging effects (Wang and Su, 2001; Pawlus et intraperitoneal injection of fermented Noni exudate (fNE) al., 2005; Su et al., 2005). Similarly, additional anticancer significantly increased the percentages of granulocytes and activities, including antiangiogenic (Hornick et al., 2003) NK cells in the peripheral blood, peritoneum, and spleen, and cancer cell-selective cytotoxic properties (Hirazumi induced complete tumor rejection in normal C57BL/6J et al., 1994; Arpornsuwan and Punjanon, 2006), suggest mice, partial tumor rejection in C57 nude mice lacking its potential as a treatment to inhibit tumor growth and functional lymphocytes, and no tumor rejection in NK progression. cell deficient beige mice. Over 85% of the C57BL/6J Also, a few in vitro and in vivo animal studies suggest mice that received fNE survived the first tumor injection a possible unidentified substance in un-pasteurized Noni and rejected up to 5x106 tumor cells when re-challenged. fruit juice that may have a small degree of anticancer These data demonstrated that fNE appears to be able to activity. The isolation of the active component warrants stimulate the innate immune system and the adaptive further research (Brown, 2012). immune system to reject tumor cells. NK cells respond Another result suggested that drinking 1-4 oz of quickly and appear to be among the major players of the TNJ daily may reduce the cancer risk in heavy cigarette innate immune system, while the adaptive immune system smokers by blocking carcinogen-DNA binding or excising reacts later with a retained memory (Li et al., 2008). DNA adducts from genomic DNA (Wang et al., 2009).

Anticancer Properties of Noni Noni and Esophageal Cancer

Complementary and alternative medicine use is Although only a few studies have tested the cancer common among cancer patients. In many surveys, herbal inhibitory actions of Noni in vivo, one recent study medicines are among the most commonly used group of demonstrated that Noni fruit powder had both preventative treatments. Herbal remedies are believed by the general and treatment efficacy on rat esophageal cancer induced public to be safe, cause less side effects, and less likely by N-nitrosomethylbenzylamine (Stoner et al., 2010). to cause dependency (Okalu and White, 2011). Search for new chemopreventive and antitumor agents that are Noni and Breast Cancer more effective but less toxic has kindled great interest in phytochemicals. Morinda citrifolia L. (Noni) is an herbal remedy with An immunomodulatory polysaccharide-rich substance promising anti-cancer properties. Approximately 41% (Noni-precipitate) from the fruit juice of Morinda of women are utilizing complementary and alternative citrifolia has been found to possess both prophylactic medicine (CAM) forms of medicine to manage their breast and therapeutic potentials against the immunomodulator cancer (Ernst, 2000; Wanchai et al., 2010), including sensitive Sarcoma 180 tumor system. The antitumor products from the Morinda citrifolia (Noni) plant. activity of Noni-ppt produced a cure rate of 25-45% in One study showed that TNJ may prevent mammary allogeneic mice and its activity was completely abolished breast cancer at the initiation stage of chemical by the concomitant administration of specific inhibitors of carcinogenesis (Clafshenkel et al., 2012). Another study macrophages (2-chloroadenosine), T cells (cyclosporine) demonstrated the anti-growth effect resulting from the or natural killer (NK) cells (anti-asialo GM1 antibody) induction of apoptosis, the active caspase-3 cells in tissues; (Furusawa et al., 2003). and decreased proliferation on Ehrlich ascites tumor Noni-ppt showed synergistic or additive beneficial grown in female Balb-c mice; thus concluding that Noni effects when combined with a broad spectrum of may be useful in the treatment of breast cancer either on chemotherapeutic drugs, including cisplatin, adriamycin, its own or in combination with doxorubicin (Taskin et al., Asian Pacific Journal of Cancer Prevention, Vol 14, 2013 4497 Rakesh Kumar Gupta and Amit Kumar Patel 2009). However, further studies are warranted to assess the DNA repair in prostate cancer cell lines (Alshawti et al., dosage and safety of using Noni fruit juice in combination 2011; Wong and Abdul, 2012); whereas, Vitamin A has with anti-cancer drugs against breast cancer; and needs to been found to enhance DNA-repair activities and the make a firm conclusion before implementing it into the subsequent removal of DNA adducts may be one of the clinical practice. mechanisms involved in vitamin A-mediated protection against cancer (Wolterbeek et al., 1995). However, the Noni and Lung & Colon Cancer effects of Flavonoids and Vitamin A, present in Noni juice, needs to be explored on DNA repair genes. Roots of Morinda citrifolia (Noni or Yor in Thai) have been used traditionally for thousands of years to Morinda citrifolia (Noni) Fruit-- treat chronic diseases such as cancer and heart disease. Photochemistry, Pharmacology, and Safety In one study, six known compounds, together with two new compounds (2 and 3) isolated from Morinda citrifolia Products derived from Noni fruit (Morinda citrifolia) (Noni) showed significant inhibitory effects on the have been commercialized in the USA since the 1990s proliferation of human lung and colon cancer cells (Lv et and are increasingly distributed all over the world. A al., 2011). large number of beneficial effects have been claimed for Noni. Fruit juice of Noni has been approved as a Novel Noni and Colorectal Cancer Food by the European Commission in 2003. One article reviewed current knowledge on the phytochemistry, Damnacanthal, an anthraquinone compound, isolated pharmacology, safety aspects of Noni fruit and Noni- from the roots of Morinda citrifolia L. (Noni), has been derived products, and health-related claims and benefits used for traditional therapy in several chronic diseases (Potterat and Hamburger, 2007). The knowledge on the including cancer. One study examined systematic chemical composition of Noni fruit has considerably approaches on the cancer-suppressing capability of increased over recent years. A number of in vitro and, Damnacanthal in colorectal tumorgenesis; and found to a certain extent, in vivo studies demonstrated a range that Damnacanthal exhibited cell growth arrest as well as of potentially beneficial effects. However, clinical data Caspase activity induction; and the pro-apoptotic protein are essentially lacking. To what extent the findings from & non-steroidal anti-inflammatory activated gene-1 experimental pharmacological studies are of potential (NAG-1) highly induced in colorectal cancer. They also clinical relevance is not clear at present. Based on a found that Damnacanthal enhanced transcription factor toxicological assessment, Noni juice was considered as CCAAT/enhancer binding protein β (C/EBPβ), which safe. Due to recent reports of cases of hepatotoxicity, the controls NAG-1 transcriptional activity. Taken together, safety issue has been re-examined in Europe. While the these results indicated that Damnacanthal increased anti- European Food Safety Authority sees no link between tumorigenic activity in human colorectal cancer cells adverse effects on liver and consumption of Noni juice, and that C/EBPβ plays a role in Damnacanthal-induced a continuing monitoring of the situation is desirable and NAG-1 expression (Nualsanit et al., 2011). some vigilance advised (Potterat and Hamburger, 2007).

Noni and Cervical Cancer Conclusion

Gupta et al. (2013) demonstrated that Noni/Cisplatin Though a large number of in vitro, and, to a by themselves and combination of Noni with Cisplatin certain extent, in vivo studies demonstrated a range of were able to induce apoptosis through the mitochondrial potentially beneficial effects; clinical data are essentially pathway, in both HeLa and SiHa cells, particularly lacking. To what extent the findings from experimental through the up-regulation of pro-apoptotic members and pharmacological studies are of potential clinical relevance down-regulation of the anti-apoptotic members. This is not clear at present; and needs to be explored yet. was accompanied by an increase in activity of caspases-9 and -3, thus primarily activating intrinsic pathway of Acknowledgements apoptosis. Hence, Noni offers potential to be used as a chemo adjuvant, especially for treatment of cervical cancer We would like to acknowledge Prerna Jain from All (Gupta et al., 2013). India Institute of Medical Sciences (AIIMS), New Delhi, India for her technical support. Noni and DNA Repair References Rats treated with a Noni juice concentrate did not show Akihisa T, Matsumoto K, Tokuda H, et al (2007). Anti- DNA repair synthesis (UDS) in primary rat hepatocytes, inflammatory and potential cancer chemopreventive nor could DNA adducts or DNA strand breaks be observed. constituents of the fruits of Morinda citrifolia (Noni). J Nat In summary, chemical analysis and genotoxicity tests Prod, 70, 754-7. revealed that Noni juice does not have a genotoxic Alitheen NB, Manaf AA, Yeap SK, et al (2010). Immunomodularory potential and that genotoxic anthraquinones do not exist effects of Damnacanthal isolated from roots of Morinda in Noni juice (Westendorf et al., 2007). elliptica. Pharm Biol, 48, 446-52. Flavonoids in citrus have been found to stimulate Alshatwi AA, Shafi G, Hasan TN, et al (2011). 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